Hyperhomocysteinemia exacerbates the development of intimal hyperplasia in Sprague-Dawley rats: Alleviation by rosiglitazone

The amino acid intermediate homocysteine (Hcy) is formed during the metabolism of methionine to cysteine. Hyperhomocysteinemia (HHcy) is recognized as an independent risk factor for coronary atherosclerosis. The circulating levels of total Hcy (tHcy) can increase due to intake of foods rich in methionine or deficiencies of vitamins such as folate, pyridoxine and cyanocobalamin, which are required for the metabolism of Hcy. In addition, mutations in the genes coding for Hcy metabolizing enzymes can contribute to an increase in tHcy levels. Clinical and epidemiological studies have shown that an elevated level of tHcy measured in serum or plasma is a strong predictor of cardiovascular disease risk, which appears to be greatest in patients who have HHcy following a methionine load. Intimal hyperplasia (IH) (intima/media [I/M] ratio) is the universal response of a vessel to injury and may result in vasoconstriction when left unattended. The effect of dietary HHcy on balloon catheter-injured carotid artery and its modulation (if any) by the peroxisome proliferator-activated receptor agonist gamma rosiglitazone was evaluated in 12-week-old female Sprague-Dawley rats fed either a control diet or a diet containing 1% L-methionine. Once the rats were established on the diet, the group that was fed 1% L-methionine was further subdivided and either given an aqueous preparation of 3 mg/kg/day rosiglitazone or the vehicle via oral gavage for one week. This was followed by surgically injuring the left carotid artery using a Maverick Over-The-Wire catheter (2.0 mm × 20 mm, 3.2F; Boston Scientific, USA). The rats were continued on their respective diets and drug regimen for 21 days postsurgery. On day 22 of the procedure, the rats were sacrificed for collection of blood, the carotid arteries and liver for biochemical and histological evaluation. Compared with controls there was a significant increase in both tHcy levels and I/M ratio in the rats fed 1% L-methionine (5.4±0.28 μM versus 32.8±3.01 μM, P<0.002; and 0.175±0.05 versus 1.05±0.23, P<0.005, respectively). The effect of rosiglitazone in rats fed the control diet was not prominent. On the other hand, administration of rosiglitazone to the rats on the 1% L-methionine diet significantly reduced the levels of serum tHcy (16.6±2.1 μM versus 32.8±3.01 μM, P<0.001); however, the tHcy levels remained significantly elevated compared with animals on the control diet (P<0.002). The group receiving the L-methionine diet plus rosiglitazone had an inhibition in the development of IH compared with those receiving the L-methionine diet alone (I/M of 0.278±0.041 versus 1.05±0.23, P<0.01). Moreover, the development of IH in the group receiving the L-methionine diet plus rosiglitazone treatment was not significantly different from that observed in the group on the control diet without rosiglitazone (0.278±0.041 versus 0.175±0.05, respectively). These findings may have important implications in deciphering the molecular mechanisms involved in the augmentation of IH in HHcy and modulation of this process by rosiglitazone.     

Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.     

The psychological and social impact of camp for children with chronic illnesses: a systematic review update

Advances in medicine have reduced mortality among children with complex medical conditions, resulting in a growing number of young patients living with chronic illnesses. Despite an improved prognosis, these children experience significant psychosocial morbidity, such as depression and anxiety. Therapeutic summer recreation camps have been proposed as an intervention to enhance quality of life among these children. The purpose of this systematic review was to assess the psychosocial impact of camp for children with chronic illnesses. A systematic review of central databases was undertaken using key words, and a rating tool – the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies – was employed to rate methodological quality. 21 studies were included in this systematic review. Although overall methodological quality was weak, camp participation appeared to offer short‐term psychosocial benefits on some parameters in children with a variety of chronic illnesses. There was some consistency in improved social outcomes, such as social interaction and acceptance. Based on the available evidence, it is premature to make robust claims regarding the psychosocial impact of camp as a therapeutic intervention. Theoretically informed camp programs, long‐term follow‐up, and incorporating camp‐based messaging into routine hospital care, may enhance the utility of camp as a potential psychosocial intervention in paediatrics.     

Natural history of postoperative heart block in congenital heart disease: Implications for pacing intervention

After half a century of major progress in congenital heart disease management, atrioventricular conduction block continues to complicate 1-3% of surgical procedures. Unless treated with an implanted pacemaker, permanent postoperative heart block is associated with 28-100% mortality. Postoperative heart block often proves to be transient, typically resolving within 10 days of onset. The duration of postoperative heart block is widely used as a key determinant for permanent pacemaker implantation. Current professional pacemaker implantation guidelines are largely based on this criterion. However, available natural history data suggest that other factors, such as residual conduction system injury, likely play a role in increasingly recognized cases of very late postoperative mortality and morbidity in patients who have experienced transient postoperative heart block. As growing numbers of congenital heart disease patients survive into adulthood, and artificial pacemaking capabilities continue to improve, it might be necessary to reconsider and refine currently accepted pacing indications for postoperative heart block.